Signals from the external microenvironment or 'niche' determine the fate of stem cells. In the hair follicle, stem cells themselves seem to act as a niche for the adjoining muscle cells that cause goosebumps.
When you are angry, cold or scared, your hairs stand up. This response is mediated by the arrector pili muscle, which runs from the bulge — the permanent portion of the hair follicle — to the skin surface. The muscle's contraction shifts the angle of the hair relative to the skin. Piloerection, or goosebumps, makes the hair a better insulator, and alters its appearance to send a message, gruff or bluff. Writing in Cell, Fujiwara et al.1 describe how the stem cells of the bulge act as a niche for these smooth muscle cells, coordinating their differentiation and ensuring their correct localization with high reproducibility. Although piloerection still seems to occur even when the muscle cells are not attached in precisely the right position, these data provide valuable insight into stem-cell biology.
The hair follicle has become a focus of research, in part because, in adults, its lower portion undergoes cycles of degeneration and regeneration. The keratinocytes that regenerate the follicle and hair shaft are derived from a stem-cell population housed in the bulge (Fig. 1).
Early observations suggested a simple model in which label-retaining cells (LRCs) — the most quiescent population of stem cells in the follicular epithelium — lie at the base of a stem-cell/progenitor-cell hierarchy2. At the outset of the regeneration phase, LRCs were thought to undergo asymmetrical division, generating transient amplifying cells — cells with less proliferative and developmental potential that ultimately form the differentiated cell types of the lower follicle and hair shaft. The LRCs reside in the bulge region that is adjacent to the attachment site of the arrector pili muscle (APM), and the APM was speculated to serve as a niche to maintain follicular stem cells.
Direct analysis of keratinocyte dynamics in the follicle has revealed a more complicated story that further emphasizes the potential importance of a niche. For instance, the most quiescent LRCs have a more restricted function in follicular regeneration (perhaps serving as a 'reserve' stem-cell pool), whereas other keratinocyte precursors in the permanent follicle have more active roles in the cyclical regeneration process3.
Moreover, asymmetrical division does not seem to be the mechanism that generates a fate-restricted progenitor that is distinct from the stem cell. Instead, position within the follicle seems to have a more essential role in the retention of stem-cell character. The cells that actively maintain the follicle are arranged both in a stem-cell zone — which encompasses the LRCs and is characterized by the expression of the marker protein CD34 — and in the secondary germ, which lies below it (Fig. 1).
The stem-cell zone is a component of the permanent follicle, whereas the secondary germ is a transient structure incorporated into the regenerating lower follicle. Notably, there is substantial flux of keratinocytes out of and into the stem-cell zone, not only in response to injury, but also with each cycle of regeneration and degeneration3,4,5. Despite all this movement, zones of gene expression and correlated biological properties are maintained. In this context, local cues might be expected to play an essential part in sustaining this follicular architecture.
Fujiwara et al.1 set out to test the function of proteins produced by stem cells and selectively deposited in the basement membrane of the bulge region. They chose nephronectin, a protein that keratinocyte stem cells deposit in the extracellular matrix of the bulge. They found that nephronectin guides the attachment of APM cells to the bulge by binding with high affinity to the α8β1 integrin receptor on the surface of these cells.
The authors report that mice lacking either nephronectin or the α8 integrin chain in their skin still form the APM in most of their follicles. But when the gene encoding nephronectin is mutated, the APM most frequently attaches slightly higher than normal on the follicle. Similarly, although in α8-deficient mice the APM usually finds its normal attachment site, it attaches higher up on the follicle more frequently than in normal animals. APM attachment close to its normal site in both mutants may be explained by the presence above the bulge of EGFL6 — another ligand that binds to the α8β1 integrin receptor, albeit with lower affinity — in nephronectin mutants, and by αv integrins on the APM, which can bind to nephronectin in the α8 mutant.
This beautifully executed analysis provides a clear picture of how APM attachment is directed to the nascent bulge. It is equally noteworthy, however, that the authors detected no defects in stem-cell activity in these mutants. (Note that this analysis was limited to the normal expression of a few markers preferentially expressed in bulge keratinocytes.)
Two questions arise from this observation. First, do these mutants shed light on the significance of relative quiescence within the stem-cell hierarchy? This question might once have seemed heretical, when quiescence was routinely assumed to be a defining character of stem cells. But as our understanding of stem cells in the follicle evolves, it is reasonable to ask if the LRCs really lie at the root of the stem-cell hierarchy. How does the abnormal location, or absence, of the APM affect LRCs? Do LRCs continue to co-localize with the APM wherever it attaches? And does relative quiescence of these cells have more to do with their interaction with the APM than with their 'stemness'? If the most quiescent cells co-localize with the APM in the nephronectin mutant, it would be worthwhile evaluating the properties displayed by these cells when they reside outside the 'normal' stem-cell zone.
The second question is, if the APM is not a niche for stem cells, what other cues maintain the stem-cell population in the bulge region? Perhaps the answer lies in the basement membrane. Proteins that are preferentially expressed by bulge keratinocytes and are deposited in the extracellular matrix are candidates to leave an adhesion marker in the bulge — to assist with the sorting of cells that return to the bulge region during the degeneration phase. Or perhaps they leave an instructive marker to promote resumption of the appropriate surface-marker profile and cell behaviour for cells that return to the bulge. Although nephronectin does not seem to fit these criteria, more rummaging in the basement membrane may identify other components that do.
It may also be worth delving deeper. The APM was one candidate for a mesenchymal niche for stem cells. The dermal papilla is the other well-characterized cluster of mesenchymal cells in the hair follicle, the activity of which is crucial for regulating follicular regeneration and morphogenesis6. However, it is physically separated from the bulge with each growth cycle and cannot serve as a niche for stem cells (Fig. 1).
Is there a third specialized group of mesenchymal cells that helps to maintain the bulge, or is this a function that is handled in the epithelium itself? Further analysis of the follicular basement membrane may provide the answer.
Fujiwara, H. et al. Cell 144, 577–589 (2011).
Sun, T.-T., Costsarelis, G. & Lavker, R. M. J. Invest. Dermatol. 96, 77S–78S (1991).
Hsu, Y. C., Pasolli, H. A. & Fuchs, E. Cell 144, 92–105 (2011).
Ito, M., Kizawa, K., Toyoda, M. & Morohashi, M. J. Invest. Dermatol. 119, 1310–1316 (2002).
Jaks, V. et al. Nature Genet. 40, 1291–1299 (2008).
Enshell-Seijffers, D., Lindon, C., Kashiwagi, M. & Morgan, B. A. Dev. Cell 18, 633–642 (2010).
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Journal of Cosmetic Dermatology (2018)
Stem Cell Reviews and Reports (2012)